Efficacy and safety of trigeminal parasympathetic pathway stimulation for dry eye: A systematic review and meta-analysis.

This study aimed to investigate the efficacy and safety of trigeminal parasympathetic pathway (TPP) stimulation in the treatment of dry eye. A comprehensive search for randomized clinical trials was performed in seven databases (MEDLINE, Embase, CENTRAL, etc.) up to 28 February 2023. After screening the suitable studies, the data were extracted and transformed as necessary. Data synthesis and analysis were performed using Review Manager 5.4, and the risk of bias and quality of evidence were evaluated with the recommended tools. Fourteen studies enrolling 1714 patients with two methods (electrical and chemical) of TPP stimulation were included. Overall findings indicate that TPP stimulation was effective in reducing subjective symptom score (standardized mean difference [SMD], -0.45; 95% confidence interval [CI], -0.63 to -0.28), corneal fluorescence staining (mean difference [MD], -0.78; 95% CI, -1.39 to -0.18), goblet cell area (MD, -32.10; 95% CI, -54.58 to -9.62) and perimeter (MD, -5.90; 95% CI, -10.27 to -1.53), and increasing Schirmer's test score (SMD, 0.98; 95% CI, 0.65 to 1.31) and tear film break-up time (SMD, 0.57; 95% CI, 0.19 to 0.95). Compared to inactive or low-activity stimulation controls, it has a higher incidence of adverse events. Therefore, TPP stimulation may be an effective treatment for dry eye, whether electrical or chemical. Adverse events are relatively mild and tolerable. Due to the high heterogeneity and low level of evidence, the current conclusions require to be further verified.

Diagnostic Value of Blink Reflex Combined with Trigeminal Somatosensory Evoked Potential in Trigeminal Neuralgia.

Objective: To explore the diagnostic value of blink reflex combined with trigeminal somatosensory evoked potential (TSEP) in trigeminal neuralgia. Methods: A total of 147 patients with trigeminal neuralgia were enrolled as the research objects between February 2022 and February 2023. After admission, all underwent blink reflex on affected/healthy sides and TSEP examinations. The diagnostic value of the blink reflex combined with TSEP was analyzed. Results: The latency of R1, R2, and R2' waves (refers to the different nerve signal waveforms that are recorded when a facial nerve conduction speed test is performed) on the affected side was significantly longer than that on the healthy side (t = 26.324, 18.391, 20.801,Ps < .001), and latency of W1, W2 and W3 waves was also significantly longer than that on the healthy side (t = 16.045, 10.814, 10.349, P < .001). The results of Pearson correlation analysis showed that the latency of R1, W1, W2, and W3 waves was positively correlated with the VAS score (r = 0.539, 0.611, 0.577, 0.586, P < .001). The results of receiver operating characteristic (ROC) curves analysis showed that area under the curve (AUC) values of R1, R2, R2', W1, W2, and W3 waves latency on the affected side in the diagnosis of trigeminal neuralgia were 0.753, 0.634, 0.651, 0.748, 0.756 and 0.736, respectively. The AUC of combined detection was 0.926, significantly greater than that of the single index (P < .001). Conclusion: Blink reflex combined with TSEP monitoring can improve the diagnostic value of trigeminal neuralgia, and the latency is related to pain.

Transcutaneous trigeminal nerve stimulation modulates the hand blink reflex.

The hand-blink reflex (HBR) is a subcortical response, elicited by the electrical stimulation of the median nerve, whose magnitude is specifically modulated according to the spatial properties of the defensive peripersonal space (DPPS) of the face. For these reasons, the HBR is commonly used as a model to assess the DPPS of the face. Little is known on the effects induced by the activation of cutaneous afferents from the face on the DPPS of the face. Therefore, we tested the effect of non-painful transcutaneous trigeminal nerve stimulation (TNS) on the amplitude of the HBR. Fifteen healthy participants underwent HBR recording before and after 20 min of sham- and real-TNS delivered bilaterally to the infraorbital nerve in two separate sessions. The HBR was recorded bilaterally from the orbicularis oculi muscles, following non-painful median nerve stimulation at the wrist. The HBR amplitude was assessed in the "hand-far" and "hand-near" conditions, relative to the hand position in respect to the face. The amplitudes of the hand-far and hand-near HBR were measured bilaterally before and after sham- and real-TNS. Real-TNS significantly reduced the magnitude of the HBR, while sham-TNS had no significant effect. The inhibitory effect of TNS was of similar extent on both the hand-far and hand-near components of the HBR, which suggests an action exerted mainly at brainstem level.

Anatomy of Trigeminal Neuromodulation Targets: From Periphery to the Brain.

The trigeminal nerve complex is a very important and somewhat unique component of the nervous system. It is responsible for the sensory signals that arise from the most part of the face, mouth, nose, meninges, and facial muscles, and also for the motor commands carried to the masticatory muscles. These signals travel through a very complex set of structures: dermal receptors, trigeminal branches, Gasserian ganglion, central nuclei, and thalamus, finally reaching the cerebral cortex. Other neural structures participate, directly or indirectly, in the transmission and modulation of the signals, especially the nociceptive ones; these include vagus nerve, sphenopalatine ganglion, occipital nerves, cervical spinal cord, periaqueductal gray matter, hypothalamus, and motor cortex. But not all stimuli transmitted through the trigeminal system are perceivable. There is a constant selection and modulation of the signals, with either suppression or potentiation of the impulses. As a result, either normal sensory perceptions are elicited or erratic painful sensations are created. Electrical neuromodulation refers to adjustable manipulation of the central or peripheral pain pathways using electrical current for the purpose of reversible modification of the function of the nociceptive system through the use of implantable devices. Here, we discuss not only the distal components, the nerve itself, but also the sensory receptors and the main central connections of the brain, paying attention to the possible neuromodulation targets.

External trigeminal nerve stimulation for drug resistant epilepsy: A randomized controlled trial.

BACKGROUND: External trigeminal nerve stimulation (ETNS) is an emergent, non-invasive neurostimulation therapy delivered bilaterally with adhesive skin electrodes. In previous studies, ETNS was associated to a decrease in seizure frequency in patients with focal drug-resistant epilepsy (DRE). OBJECTIVE: To determine the long-term efficacy and tolerability of ETNS in patients with focal DRE. Moreover, to explore whether its efficacy depends on the epileptogenic zone (frontal or temporal), and its impact on mood, cognitive function, quality of life, and trigeminal nerve excitability. METHODS: Forty consecutive patients with frontal or temporal DRE, unsuitable for surgery, were randomized to ETNS or usual medical treatment. Participants were evaluated at 3, 6 and 12 months for efficacy, side effects, mood scales, neuropsychological tests and trigeminal nerve excitability. RESULTS: Subjects had a median of 15 seizures per month and had tried a median of 12.5 antiepileptic drugs. At 12 months, percentage of responders was 50% in ETNS group and 0% in control group. Seizure frequency in ETNS group decreased by -43.5% from baseline. Temporal epilepsy subgroup responded better than frontal epilepsy subgroup (55.56% vs. 45.45%, respectively). Median stimulation intensity was 6.2 mA. ETNS improved quality of life, but not anxiety or depression. Long-term ETNS affected neither neuropsychological function, nor trigeminal nerve excitability. No relevant adverse events were observed. CONCLUSIONS: ETNS is an effective and well-tolerated therapy for focal DRE. Patients with temporal epilepsy showed a better response than those with frontal epilepsy. Future studies with larger populations may define its role compared to other neurostimulation techniques. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that ETNS reduces seizure frequency in patients with focal DRE.

Noninvasive vagus nerve stimulation and the trigeminal autonomic reflex: An fMRI study.

OBJECTIVE: The trigeminal autonomic reflex is a physiologic reflex that plays a crucial role in primary headache and particularly in trigeminal autonomic cephalalgias, such as cluster headache. Previous studies have shown that this reflex can be modulated by the vagus nerve, leading to an inhibition of the parasympathetic output of the reflex in healthy participants. The aim of the present study was to characterize neural correlates of the modulatory effect of noninvasive vagus nerve stimulation (nVNS) on the trigeminal autonomic reflex. METHODS: Twenty-one healthy participants were included in a 2-day, randomized, single-blind, within-subject design. The reflex was activated inside the MRI scanner using kinetic oscillation stimulation placed in the left nostril, resulting in an increase in lacrimation. After the first fMRI session, the participants received either sham vagus nerve stimulation or nVNS outside the scanner and underwent a subsequent fMRI session. RESULTS: nVNS prompted an increase in activation of the left pontine nucleus and a decreased activation of the right parahippocampal gyrus. Psychophysiologic interaction analyses revealed an increased functional connectivity between the left pontine nucleus and the right hypothalamus and a decreased functional connectivity between the right parahippocampal gyrus and the bilateral spinal trigeminal nuclei (sTN). CONCLUSIONS: These findings indicate a complex network involved in the modulatory effect of nVNS including the hypothalamus, the sTN, the pontine nucleus, and the parahippocampal gyrus.

Hypothalamic activation discriminates painful and non-painful initiation of the trigeminal autonomic reflex - an fMRI study.

BACKGROUND: The role of the trigeminal autonomic reflex in headache syndromes, such as cluster headache, is undisputed but sparsely investigated. The aim of the present study was therefore, to identify neural correlates that play a role in the initiation of the trigeminal autonomic reflex. We further aimed to discriminate between components of the reflex that are involved in nociceptive compared to non-nociceptive processing. METHODS: Kinetic Oscillation Stimulation (KOS) in the left nostril was applied in order to provoke autonomic symptoms (e.g. lacrimation) via the trigeminal autonomic reflex in 26 healthy participants using functional magnetic resonance imaging. Unpleasantness and painfulness were assessed on a visual analog scale (VAS), in order to assess the quality of the stimulus (e.g. pain or no pain). RESULTS: During non-painful activation, specific regions involved in the trigeminal autonomic reflex became activated, including several brainstem nuclei but also cerebellar and bilateral insular regions. However, when the input leading to activation of the trigeminal autonomic reflex was perceived as painful, activation of the anterior hypothalamus, the locus coeruleus (LC), the ventral posteriomedial nucleus of the thalamus (VPM), as well as an activation of ipsilateral insular regions, was observed. CONCLUSION: Our results suggest the anterior hypothalamus, besides the thalamus and specific brain stem regions, play a significant role in networks that mediate autonomic output (e.g. lacrimation) following trigeminal input, but only if the trigeminal system is activated by a stimulus comprising a painful component.

External trigeminal nerve stimulation: Potential rescue treatment for acute vestibular migraine.

OBJECTIVE: Vestibular migraine (VM) is the most common neurologic cause of vertigo among adults. However, there are no specifically studied or approved rescue therapies for acute VM attacks. This study describes how external trigeminal nerve stimulation (eTNS) using the Cefaly® (CEFALY Technology, Seraing, Belgium) device relieves acute VM episodes. METHODS: Single-center, retrospective review of 19 patients with acute VM attacks (seen between May 2018 and June 2019) treated with 20-min eTNS. Prior to treatment, patients graded the severity of their vertigo/headache using a 10-point visual analog scale (VAS) with 0 representing no vertigo/headache, and 10 representing the worst imaginable vertigo/headache. After eTNS, patients graded their vertigo/headache using the same VAS 15 min. In addition, bedside neuro-otologic examination was performed before and after treatment. RESULTS: 19/19 patients reported improvement in vertigo severity. Mean vertigo severity was 6.6 (±2.1; median 7) before eTNS, and 2.7 (±2.6; median 3) following treatment; mean improvement in vertigo was 61.3% (±32.6; median 50.0%). During VM episodes, 14/19 experienced headache. Mean headache severity was 4.8 (±2.4; median 4.5) before eTNS, and was 1.4 (±2.4; median 0) following treatment; mean improvement in headache was 77.2% (±32.7; median 100.0%). Neuro-otologic examination was normal during VM attacks in all except Patient 7 who had spontaneous upbeat nystagmus which resolved after eTNS. Other improvements include improvement of eye pressure, head pressure, and chronic facial pain. No intolerable side effects were reported. CONCLUSION: This study provides preliminary evidence that eTNS is a novel, non-invasive, safe and effective treatment for acute VM attacks.

Flexible, multichannel cuff electrode for selective electrical stimulation of the mouse trigeminal nerve.

The trigeminal nerve (cranial nerve V), along with other cranial nerves, has in recent years become a popular target for bioelectric medicine due to its direct access to neuromodulatory centers. Trigeminal nerve stimulation is currently being evaluated as an adjunctive treatment for various neurodegenerative and neuropsychiatric diseases despite the mechanism of action being in question. In this work, we describe the development and validation of a novel neural interface for the infraorbital branch of the trigeminal nerve utilizing a thin film (TF) nerve cuff containing multiple electrode sites allowing for more selective stimulation of the nerve. We characterized the properties of the device using electrochemical impedance spectroscopy, cyclic voltammetry, voltage excursions, and in vivo testing. Electrochemical measurements demonstrate that the platinum-based electrodes possess a capacitive charge carrying mechanism suitable for stimulation of biological tissue with a safe charge injection limit of 73.13 µC/cm2. In vivo stimulation experiments show that the TF cuff can reliably stimulate nerve targets eliciting cortical responses similar to a silicone cuff electrode. Furthermore, selecting different pairs of stimulation electrodes on the TF cuff modulated the magnitude and/or spatial pattern of cortical responses suggesting that the device may be able to selectively stimulate different parts of the nerve. These results suggest that the TF cuff is a viable neural interface for stimulation of the infraorbital branch of the trigeminal nerve that enables future research examining the therapeutic mechanisms of trigeminal nerve stimulation.

Percutaneous Trigeminal Nerve Stimulation for Persistent Idiopathic Facial Pain: A Case Series.

BACKGROUND: Persistent idiopathic facial pain (PIFP) can be refractory to conventional management approaches. Neuromodulatory procedures such as percutaneous trigeminal nerve stimulation (TNS) have been sparsely reported as potential treatment options for amelioration of debilitating refractory pain associated with PIFP. The present study investigated the use of percutaneous TNS in a series of patients with PIFP to evaluate the potential efficacy of pain relief. METHODS: We performed a retrospective medical record review for patients with PIFP who had presented to Emory University Hospital and had undergone TNS for PIFP. The primary outcomes were postoperative pain using the visual analog scale (VAS) for pain and morphine equivalent use. Descriptive statistics, mean ± standard deviation, and the nonparametric Wilcoxon sign rank test were used, as appropriate. A P value of <0.05 was considered statistically significant. RESULTS: A total of 23 patients underwent percutaneous TNS for PIFP. Of the 23 patients, 20 (86.9%) reported a >50% improvement after trial stimulation. Of the patients who had received permanent TNS implants, 13 of 17 (76.4%) had VAS scores available. For these patients, the mean preoperative VAS score had decreased from 5.69 ± 2.09 to 0.15 ± 0.55 postoperatively. The VAS scores displayed a statistically significant decrease after TNS (P = 0.0014). A subset of 9 patients with available data also demonstrated a significant reduction in morphine equivalent use after TNS (before, 50.54 ± 51.30; after, 25.83 ± 33.58; P = 0.048). CONCLUSION: The results from the present study have indicated that percutaneous stimulation of the trigeminal nerve is efficacious in the treatment of PIFP and can significantly decrease morphine equivalent use. Further longitudinal studies are required to validate our results.

Effect of short-term transcutaneous trigeminal nerve stimulation on EEG activity in drug-resistant epilepsy.

BACKGROUND: Transcutaneous trigeminal nerve stimulation (TNS) has antiepileptic effects in patients with drug-resistant epilepsy (DRE). However, whether and how TNS is able to modulate the electroencephalogram (EEG) background activity in patients with DRE is still unknown. OBJECTIVES: To investigate the effect of short-term TNS on EEG background activity in DRE by qualitative and quantitative analyses. METHODS: Twenty-nine DRE patients participated in the study. Twenty-two were randomly divided into a "sham-TNS" or "real-TNS" group; seven patients underwent stimulation of the median nerve (MNS) at the wrist. Real-TNS was delivered bilaterally to the infraorbital nerve (trains of 1-20 mA, 120 Hz, cyclic modality for 20 min). The sham-TNS protocol mimicked the real-TNS one but at a zero intensity. For MNS, the same parameters as real-TNS were used. EEG was continuously acquired for 40 min: 10' pre, 20' during and 10' post stimulation. EEG was visually inspected for interictal epileptiform discharge (IEDs) changes and processed by spectral analysis for changes in mean frequency and absolute power of each frequency band. RESULTS: A significant increase of EEG absolute alpha power was observed during real-TNS compared with the sham-TNS (F34,680 = 1.748; p = 0.006). Conversely, no significant effects were noticed either for quantitative analysis of other frequency bands or for IEDs detection. MNS proved unable to modulate EEG activity. CONCLUSIONS: Short-term TNS induces an acute and specific effect on background EEG of DRE by increasing the absolute alpha band power. EEG alpha rhythm enhancement may index a cortical functional inhibition and act as a seizure-preventing mechanism.

Double-Blind, Sham-Controlled, Pilot Study of Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Trigeminal nerve stimulation (TNS), a minimal-risk noninvasive neuromodulation method, showed potential benefits for attention-deficit/hyperactivity disorder (ADHD) in an unblinded open study. The present blinded sham-controlled trial was conducted to assess the efficacy and safety of TNS for ADHD and potential changes in brain spectral power using resting-state quantitative electroencephalography. METHOD: Sixty-two children 8 to 12 years old, with full-scale IQ of at least 85 and Schedule for Affective Disorders and Schizophrenia-diagnosed ADHD, were randomized to 4 weeks of nightly treatment with active or sham TNS, followed by 1 week without intervention. Assessments included weekly clinician-administered ADHD Rating Scales (ADHD-RS) and Clinical Global Impression (CGI) scales and quantitative electroencephalography at baseline and week 4. RESULTS: ADHD-RS total scores showed significant group-by-time interactions (F1,228 = 8.12, p = .005; week 4 Cohen d = 0.5). CGI-Improvement scores also favored active treatment (χ21,168 = 8.75, p = .003; number needed to treat = 3). Resting-state quantitative electroencephalography showed increased spectral power in the right frontal and frontal midline frequency bands with active TNS. Neither group had clinically meaningful adverse events. CONCLUSION: This study demonstrates TNS efficacy for ADHD in a blinded sham-controlled trial, with estimated treatment effect size similar to non-stimulants. TNS is well tolerated and has minimal risk. Additional research should examine treatment response durability and potential impact on brain development with sustained use. CLINICAL TRIAL REGISTRATION INFORMATION: Trigeminal Nerve Stimulation for ADHD; http://clinicaltrials.gov/; NCT02155608.

Acute migraine therapy with external trigeminal neurostimulation (ACME): A randomized controlled trial.

OBJECTIVE: To assess the safety and efficacy of external trigeminal nerve stimulation for acute pain relief during migraine attacks with or without aura via a sham-controlled trial. METHODS: This was a double-blind, randomized, sham-controlled study conducted across three headache centers in the United States. Adult patients who were experiencing an acute migraine attack with or without aura were recruited on site and randomly assigned 1:1 to receive either verum or sham external trigeminal nerve stimulation treatment (CEFALY Technology) for 1 hour. Pain intensity was scored using a visual analogue scale (0 = no pain to 10 = maximum pain). The primary outcome measure was the mean change in pain intensity at 1 hour compared to baseline. RESULTS: A total of 109 participants were screened between February 1, 2016 and March 31, 2017. Of these, 106 patients were randomized and included in the intention-to-treat analysis (verum: n = 52; sham: n = 54). The primary outcome measure was significantly more reduced in the verum group than in the sham group: -3.46 ± 2.32 versus -1.78 ± 1.89 ( p < 0.0001), or -59% versus -30% ( p < 0.0001). With regards to migraine subgroups, there was a significant difference in pain reduction between verum and sham for 'migraine without aura' attacks: mean visual analogue scale reduction at 1 hour was -3.3 ± 2.4 for the verum group versus -1.7 ± 1.9 for the sham group ( p = 0.0006). For 'migraine with aura' attacks, pain reduction was numerically greater for verum versus sham, but did not reach significance: mean visual analogue scale reduction at 1 hour was -4.3 ± 1.8 for the verum group versus -2.6 ± 1.9 for the sham group ( p = 0.060). No serious adverse events were reported and five minor adverse events occurred in the verum group. CONCLUSION: One-hour treatment with external trigeminal nerve stimulation resulted in significant headache pain relief compared to sham stimulation and was well tolerated, suggesting it may be a safe and effective acute treatment for migraine attacks. STUDY PROTOCOL: ClinicalTrials.gov Identifier: NCT02590939.

Efficacy and mode of action of external trigeminal neurostimulation in migraine.

INTRODUCTION: Available preventive drug treatments for migraine lack complete efficacy and often have unpleasant adverse effects. Hence, their clinical utility and therapeutic adherence are limited. Noninvasive neurostimulation methods applied over various peripheral sites (forehead, mastoid, upper arm, cervical vagus nerve) have raised great interest because of their excellent efficacy/tolerance profile. Among them external trigeminal nerve stimulation (eTNS) was first to obtain FDA approval for migraine therapy. Areas covered: All clinical trials of eTNS as preventive or acute migraine treatment published in extenso or presented at congresses are reviewed. The paper analyzes neuroimaging and neurophysiological studies on mechanisms of action of eTNS. As many of these studies point toward the anterior cingulate cortex (ACC) as a likely eTNS target, the paper scrutinizes the available literature on the ACC implication in migraine pathophysiology. Expert commentary: eTNS is a viable alternative to standard pharmacological antimigraine strategies both for prevention and abortive therapy. eTNS could chiefly exert its action by modulating the perigenual ACC, which might also be of interest for treating other disorders like fibromyalgia or depression. It remains to be determined if this might be a common mechanism to other peripheral noninvasive neurostimulation methods.

Local anesthetic effect of docosahexaenoic acid on the nociceptive jaw-opening reflex in rats.

Although docosahexaenoic acid (DHA) administration suppresses sodium channels in primary afferent sensory neurons, the acute local effect of DHA on the trigeminal nociceptive reflex remains to be elucidated, in vivo. Therefore, the aim of the present study was to investigate whether local administration of DHA attenuates the nociceptive jaw-opening reflex (JOR) in vivo in the rat. The JOR evoked by electrical stimulation of the tongue was recorded by a digastric muscle electromyogram (dEMG) in pentobarbital-anesthetized rats. The amplitude of the dEMG response was significantly increased in proportion to the electrical stimulation intensity (1-5 x threshold). At 3 x threshold, local administration of DHA (0.1, 10 and 25 mM) dose-dependently inhibited the dEMG response, and lasted 40 min. Maximum inhibition of the dEMG signal amplitude was seen within approximately 10 min. The mean magnitude of inhibition of the dEMG signal amplitude by DHA (25 mM) was almost equal to the local anesthetic, 1% lidocaine (37 mM), a sodium channel blocker. These findings suggest that DHA attenuates the nociceptive JOR via possibly blocking sodium channels, and strongly support the idea that DHA is a potential therapeutic agent and complementary alternative medicine for the prevention of acute trigeminal nociception.

An audit of external trigeminal nerve stimulation (eTNS) in epilepsy.

PURPOSE: External trigeminal nerve stimulation (eTNS) is a non-invasive neurostimulation treatment for drug refractory epilepsy. There is limited published data on the efficacy of eTNS and none relating to quality of life, mood or effect on sleep quality. METHODS: We audited its use in 42 patients with drug refractory epilepsy at a tertiary centre, between 02/04/2013 and 14/08/2015. Data was collected on seizure frequency, quality of life, mood and sleep quality before and after initiating treatment. RESULTS: 45% of patients continued to use eTNS at the end of the audit period. We observed a significant improvement in both quality of life and mood in those without intellectual disabilities. A decrease in seizures (-11.0%, min -60, max +65) was observed though this did not reach statistical significance with the relatively small numbers available for analysis. CONCLUSION: Further controlled studies are required to confirm the efficacy of eTNS. However, as it is non-invasive, flexible and safe eTNS can be considered as an option in patients with drug refractory epilepsy.

Neuroprotective Effects of Trigeminal Nerve Stimulation in Severe Traumatic Brain Injury.

Following traumatic brain injury (TBI), ischemia and hypoxia play a major role in further worsening of the damage, a process referred to as 'secondary injury'. Protecting neurons from causative factors of secondary injury has been the guiding principle of modern TBI management. Stimulation of trigeminal nerve induces pressor response and improves cerebral blood flow (CBF) by activating the rostral ventrolateral medulla. Moreover, it causes cerebrovasodilation through the trigemino-cerebrovascular system and trigemino-parasympathetic reflex. These effects are capable of increasing cerebral perfusion, making trigeminal nerve stimulation (TNS) a promising strategy for TBI management. Here, we investigated the use of electrical TNS for improving CBF and brain oxygen tension (PbrO2), with the goal of decreasing secondary injury. Severe TBI was produced using controlled cortical impact (CCI) in a rat model, and TNS treatment was delivered for the first hour after CCI. In comparison to TBI group, TBI animals with TNS treatment demonstrated significantly increased systemic blood pressure, CBF and PbrO2 at the hyperacute phase of TBI. Furthermore, rats in TNS-treatment group showed significantly reduced brain edema, blood-brain barrier disruption, lesion volume, and brain cortical levels of TNF-α and IL-6. These data provide strong early evidence that TNS could be an effective neuroprotective strategy.

Effect of Topical Anesthesia Using an Adhesive Patch and Anesthetic Solution.

We analyzed trigeminal somatosensory evoked potentials (TSEP) to the alveolar mucosa to investigate the efficacy of an amide local anesthetic, 2% lidocaine hydrochloride with 12.5 µg/mL epinephrine (Lido treatment) as a topical anesthetic. Eighteen consenting healthy adult volunteers were enrolled. A volume of 0.06 mL of Lido, 0.06 g of 20% benzocaine, or 0.06 mL of physiological saline (control) was instilled onto a hemostatic adhesive patch, which was then applied to the alveolar mucosa at the maxillary right canine for 5 minutes. An electrical stimulus approximately 5 times that of the sensory threshold was applied using a surface stimulation electrode. The trigeminal somatosensory evoked potential was recorded immediately, 5 minutes, and 10 minutes after removal of the patch. Positive P125 and P310 peaks and negative N100 and N340 peaks were observed as a result of the electrical stimulation. A significant decrease in the percentage change in amplitude of N100-P125 was observed in the Lido treatment immediately, 5 minutes, and 10 minutes after patch removal. In the Lido treatment, trigeminal somatosensory evoked potential amplitude at N100-P125 decreased significantly, suggesting that topical anesthesia produced by an amide local anesthetic may have a topical anesthetic effect as potent as that produced by an ester local anesthetic.

Sensory trigeminal ULF-TENS stimulation reduces HRV response to experimentally induced arithmetic stress: A randomized clinical trial.

Ultra Low Frequency Transcutaneous Electric Nervous Stimulation (ULF-TENS) is extensively used for pain relief and for the diagnosis and treatment of temporomandibular disorders (TMD). In addition to its local effects, ULF-TENS acts on the autonomic nervous system (ANS), with particular reference to the periaqueductal gray (PAG), promoting the release of endogenous opioids and modulating descending pain systems. It has been suggested that the PAG participates in the coupling between the emotional stimulus and the appropriate behavioral autonomic response. This function is successfully investigated by HRV. Therefore, our goal is to investigate the effects of trigeminal ULF-TENS stimulation on autonomic behavior in terms of HRV and respiratory parameters during an experimentally-induced arithmetic stress test in healthy subjects. Thirty healthy women between 25 and 35years of age were enrolled and randomly assigned to either the control (TENS stimulation off) or test group (TENS stimulation on). Heart (HR, LF, HF, LF/HF ratio, DET, RMSSD, PNN50, RR) and respiratory (BR) rate were evaluated under basal, T1 (TENS off/on), and stress (mathematical task) conditions. Results showed that HRV parameters and BR significantly changed during the arithmetic stress paradigm (p<0.01). Independently of stress conditions, TENS and control group could be discriminated only by non-linear HRV data, namely RR and DET (p=0.038 and p=0.027, respectively). During the arithmetic task, LF/HF ratio was the most sensitive parameter to discriminate between groups (p=0.019). Our data suggest that trigeminal sensory ULF-TENS reduces the autonomic response in terms of HRV and BR during acute mental stress in healthy subjects. Future directions of our work aim at applying the HRV and BR analysis, with and without TENS stimulation, to individuals with dysfunctional ANS among those with TMD.